There are many pharmaceuticals that are known to be highly effective for the treatment of debilitating diseases such as cancer. Unfortunately, many of these pharmaceuticals are not stable to commercial shipping and storage conditions, which may include temperatures above 23° C. (ambient room temperature) and/or relative humidities greater than ambient. In an effort to preserve the integrity of the pharmaceutical, non-routine shipping and storage conditions are sometimes employed. For example, the pharmaceutical is shipped and stored at refrigerated temperatures, under an inert atmosphere, and/or it is provided with instructions to use or discard within just a few days of receipt. Oftentimes, the pharmaceutical must be discarded because it has not retained sufficient integrity during the shipping and storage process. This is undesirable because these sensitive pharmaceuticals are generally developed and manufactured at great expense.
Lyophilization, or “freeze-drying,” is a method used in the manufacture of pharmaceuticals. Many technical challenges, for example, identifying appropriate shelf temperatures, product temperatures, vacuum levels, freezing, primary drying parameters, and secondary drying parameters, must be overcome in the development of a commercially viable lyophilization process. In addition, the pharmaceutical is usually sensitive to the lyophilization process, which typically involves the use of water. Moreover, lyophilization usually involves the addition of pharmaceutical excipients, such as bulking agents and the like. The sensitivity of the particular pharmaceutical to excipients is generally unknown and must be exhaustively evaluated.
Another factor in identifying a suitable lyophilization process is the evaluation of the properties of the lyophilized “cake” that is produced. The cake must be stable to the storage and shipping conditions for a reasonable about of time. Additionally, if the pharmaceutical is for injection, the lyophilized cake should be readily reconstituted with an appropriate intravenous solution such as Sodium Chloride for Injection, Sterile Water for Injection, Mannitol I.V., and the like, to form a particulate-free injectable solution. Indeed, lyophilized cakes that do not readily form a clear solution with little to no particulate matter must be discarded.
As such, lyophilization conditions and methods for producing stable, readily reconstitutable lyophilized proteasome inhibitors are needed.